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Background: Inrecentdecades,theassessmentofneurologicalsoftsigns(NSS)inpatientswithpsychosis has become a subject of special interest. The study of the progression of NSS during adolescence will provide valuable information about the role of NSS as endophenotypes or biomarkers and about brain development at a stage in which brain maturation has not yet been completed. Methods: Neurological soft signs were assessed in a sample of 110 first episodes of early-onset psychosis (EOP) and 98 healthy children and adolescents at two different times in a 2-year follow-up period. Results: Patients with EOP showed more NSS than controls both at baseline (p < .001) and the 2-year follow-up (p < .001). No differences were found in the number of signs among the different diagnostic subgroups (schizophrenia, bipolar disorder, and other psychoses). When we examined the changes in NSS over the follow-up, the reduction of NSS in the patients was greater than the controls for ‘Motor coordination’ (p = .032), ‘Others’ (p < .001), and ‘Total score’ (p < .001) of the NES. Conclusion: Despite the greater reduction of NSS in patients than in controls along the follow-up, patients still have more neurological signs than healthy controls; therefore, these signs may be considered a trait marker. NSS do not seem to be specific to schizophrenia as they are present in different EOPs. Keywords: Neurological soft signs, children and adolescents, psychosis, neurodevelopment.

[FR] L’objectif du présent article est de passer en revue les études longitudinales évaluant des changements cérébraux évolutifs chez des patients souffrant de psychose précoce. Comprendre les trajectoires développementales des processus moléculaires et cellulaires du développement normal, et les différences entre le développement normal et anormal, est essentiel pour l’interprétation des études d’imagerie clinique, et pour la recherche d’une physiopathologie différentielle dans les affections psychiatriques liées au neurodéveloppement. Par conséquent, compte tenu de l’objectif de cet article, nous présenterons un bref sommaire des résultats d’études d’imagerie à résonnance magnétique (IRM) chez des sujets à développement cérébral normal. Nous présenterons ensuite un bref sommaire d’études longitudinales portant sur des psychoses précoces. Étant donné que la schizophrénie à début très précoce et la schizophrénie débutant à l’adolescence semblent se caractériser par des précurseurs et une évolution différents, et que l’expression génique diffère dans les différents groupes d’âge, nous diviserons les données en 2 groupes : début précoce et début à l’adolescence. Les résultats d’études longitudinales portant sur d’autres psychoses précoces seront examinés également afin d’évaluer la spécificité des résultats pour la schizophrénie, comparativement à d’autres maladies précoces avec symptômes psychotiques. Le sommaire des résultats sera suivi par des facteurs cliniques corrélés, et par une discussion des implications. Enfin, on soumettra des recommandations pour la recherche future., [EN] Progressive losses of cortical grey-matter volumes and increases in ventricular volumes have been reported in patients with childhood-onset schizophrenia (COS) during adolescence. Longitudinal studies suggest that the rate of cortical loss seen in COS during adolescence plateaus during early adulthood. Patients with first-episode adolescent onset schizophrenia show less marked progressive changes, although the number of studies in this population is small. Some studies show that, although less exaggerated, progressive changes are also present in non-schizophrenia early onset psychosis. The greater loss of brain tissue seen in COS, even some years after the first episode, as compared to adolescent- or adult-onset schizophrenia may be due to variables such as sample bias (more severe, treatment refractory sample of childhood-onset patients studied), a process uniquely related to adolescent development in COS, differential brain effects of drug treatment in this population, clinical outcome, or interactions among these variables. Findings from both cross-sectional studies of first-episode patients and longitudinal studies in COS and adolescent onset support the concept of early-onset schizophrenia as a progressive neurodevelopmental disorder with both early and late developmental abnormalities. Future studies should look for correlates at a cellular level and for pathophysiological explanations of volume changes in these populations. The association of risk genes involved in circuitries associated with schizophrenia and their relationship to developmental trajectories is another promising area of future research., [ES] Se han observado en la adolescencia unas pérdidas progresivas de volúmenes de sustancia gris y unos crecimientos ventriculares en pacientes con esquizofrenias de la niñez. Estudios longitudinales demuestran que en la adolescencia el ritmo de pérdida cortical observado en las esquizofrenias con inicios muy tempranos (COS) se estabiliza en los jóvenes adultos. Los pacientes en quienes el primer episodio sobreviene en la adolescencia presentan cambios evolutivos menos marcados, a pesar del reducido número de estudios en esta población. Ciertos estudios demuestran que unos cambios evolutivos menos marcados aparecen también en las psicosis no esquizofrénicas tempranas. La mayor pérdida de tejido cerebral observada en las esquizofrenias muy tempranas, aun varios años tras el primer episodio en comparación con las esquizofrenias de la adolescencia o la edad adulta podría estar vinculada con unas variables tales como el muestreo sesgado (enfermedad más severa; muestreo de pacientes con esquizofrenia temprana, refractarios al tratamiento), índole específica de la evolución en la adolescencia de las COS, efectos diferenciales de tratamientos medicamentosos en esta población, desenlace clínico, o interacción entre estas variables. Los resultados de estudios transversales en pacientes tras un primer episodio, así como estudios longitudinales sobre las COS y las esquizofrenias con inicio en la adolescencia, afianzan la idea que la esquizofrenia temprana es una afección del neurodesarrollo evolutiva, con anomalías del desarrollo tempranas y tardías. Los fururos estudios deberían buscar factores relacionados a nivel celular, y explicaciones patofisiolológicas para los cambios de volumen en estas poblaciones. La asociación de genes con crecimiento del riesgo en los circuitos neuronales vinculados con la esquizofrenia en relación con las trayectorias del desarrollo es otra pista prometedora para las investigaciones del porvenir., Cette recherche est soutenue en partie par CIBER de Salud Mental, ISCIII, Espagne.

BackgroundThe correlates of insight in early-onset psychosis have received little previous attention.MethodWe studied clinical correlates of insight in a sample of 110 adolescent recent-onset psychosis patients (mean age 15.53 years; psychotic symptoms present for ResultsInsight improved over the early phases of the illness, in parallel with psychopathological improvement. Poor insight at baseline and 6 months correlated with poor functioning at 6 and 12 months respectively. Schizophrenia patients had poorer insight than patients with bipolar disorder at 6 and 12 months but not at baseline. Logistic and linear regressions were used to predict 12-month diagnoses and functioning based on insight measurements. Baseline awareness of illness was a significant predictor for diagnosis [odds ratio (OR) 1.4, 95% confidence interval (CI) 1.05–1.97]. Treatment compliance at 6 months did not correlate with baseline SUMD subscores, but correlated with insight into having a disorder (Spearman's ρ=0.21,p=0.039), its consequences (Spearman's ρ=0.28,p=0.006) and the need for treatment (Spearman's ρ=0.26,p=0.012) at 6 months. The ‘attribution of symptoms’ dimension of insight is poorly correlated with other insight dimensions and with other clinical variables.ConclusionsPoor insight correlates with symptom severity and global functioning but also has some trait value for schizophrenia, which is apparent once acute psychotic symptomatology is not prominent. A multi-dimensional approach to the assessment of insight is necessary, as different dimensions are influenced by different factors.

BackgroundGlutamatergic neurotransmission dysfunction has classically been related to the aetiology of psychotic disorders. A substantial polygenic component shared across these disorders has been reported and molecular genetics studies have associated glutamatergic-related genes, such as d-amino acid oxidase activator (DAOA) and regulator of G-protein signalling 4 (RGS4) with the risk for psychotic disorders. Our aims were to examine: (i) the relationship between DAOA and RGS4 and the risk for psychotic disorders using a family-based association approach, and (ii) whether variations in these genes are associated with differences in patients’ cognitive performance.MethodsThe sample comprised 753 subjects (222 patients with psychotic disorders and 531 first-degree relatives). Six SNPs in DAOA and 5 SNPs in RGS4 were genotyped. Executive cognitive performance was assessed with Trail Making Test B (TMT-B) and Wisconsin Card Sorting Test (WCST). Genetic association analyses were conducted with PLINK, using the transmission disequilibrium test (TDT) for the family-based study and linear regression for cognitive performance analyses.ResultsThe haplotype GAGACT at DAOA was under-transmitted to patients (P = 0.0008), indicating its association with these disorders. With regards to cognitive performance, the DAOA haplotype GAGGCT was associated with worse scores in TMT-B (P = 0.018) in SZ patients only. RGS4 analyses did not report significant results.ConclusionsOur findings suggest that the DAOA gene may contribute to the risk for psychotic disorders and that this gene may play a role as a modulator of executive function, probably through the dysregulation of the glutamatergic signalling.

BackgroundEarly-onset first-episode psychosis (FEP) and high functioning autism spectrum disorders (ASD) are complex neuro–developmental disorders that share symptomatology but it is not clear if they also share neurobiological abnormalities (Chisholm et al., 2015). We examined thickness, surface area and volume in a direct comparison of children and adolescents with FEP (onset before 18 years), high-functioning ASD, and healthy subjects.MethodsMagnetic resonance imaging scans of 85 participants (30 ASD, 29 FEP, 26 healthy controls, age range 10–18 years) were obtained from the same MR scanner using the same acquisition protocol. The FreeSurfer analysis suite was used to quantify vertex-wise estimates of the metrics thickness, surface area, and volume.ResultsASD and FEP had spatially overlapping insular deficits for each metric. The transdiagnostic overlap of deficits was greatest for volume (55% of all insular vertices) and smallest for thickness (18%). Insular thickness and surface area deficits did not overlap in ASD and overlapped only in 8% of all insular vertices in FEP.ConclusionsMorphological insular deficits are common to FEP and high functioning ASD when compared to healthy participants. The pattern of deficits was similar in both disorders, i.e. a largely non-overlap of insular thickness and surface area. The non-overlap provides further evidence that these metrics represent two independent outcomes of corticogenesis, both of which are affected in FEP and ASD.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Diagnosis of schizophrenia spectrum disorders (SSD) may be difficult in clinical practice, particularly during the first episodes of early-onset psychosis (FE-EOP). Aims To develop a Support Vector Machine (SVM) algorithm as a predictive tool for diagnostic outcome in patients with FE-EOP, based on clinical and biomedical data at the emergence of the illness. Methods Two-year, prospective longitudinal study, where 81 patients (9-17 years of age) with a FE-EOP and stable diagnosis at follow-up and 41 age and sex-matched healthy controls (HC) were included. Structured diagnostic interviews, clinical and cognitive scales, a MRI scan and biochemical tests were conducted at baseline. Three SVM classification algorithms were developed (SSD vs HC group, non-SSD vs HC group, and SSD vs non-SSD group). Jackknifing was used to validate the algorithms and to calculate performance estimates. Enhanced-Recursive Feature Elimination was performed in order to gain information about the predictive weight for diagnosis of each variable. Results The SSD-versus-non-SSD classifier achieved an overall accuracy of 83.1%, sensitivity of 86.6% and specificity of 77.8%. The variables during a FE-EOP with higher predictive value for a diagnosis of SSD were clinical variables such as negative symptoms preceding or during the psychotic onset, poor insight and duration of illness until first psychiatric contact. Biochemical, neuroimaging, and cognitive variables at baseline did not provide any additional predictive value. Conclusions SVM may serve as a predictive tool for early diagnosis of SSD during a FE-EOP. The most discriminative variables during a FE-EOP for a future diagnosis of SSD are clinical variables.

IntroductionPro/antiinflammatory imbalance has been found in first-episode psychotic (FEP) patients, even 12 months later. Current research is every time more focused in the need to find biomarkers to understand the underlying pathophysiological mechanisms of this severe illness.ObjectivesTo assess peripherical levels of neurotrophins and their receptors and their correlation with inflammation, clinical symptomatology and response to antipsychotic treatment, over the time.MethodologyNinety-four FEP patients and 80 matched healthy controls were included. Blood samples were taken at baseline to measure BDNF and NGF and their receptor levels (TrkB-full, TrkB-truncated and TrkA) and pro/antiinflammatory parameters (NFkB, COX-2, iNOS, PPARgamma, 15d-PG12). Patients were followed-up during 12 months.ResultsBDNF TrkB-full receptor and NFG TrkA receptor levels increased during the follow-up whereas BDNF TrkB-truncated form receptor decreased. After adjusting for confounding variables, baseline levels of proinflamatory variables were significantly related to TrkB-full/TrkB-truncated ratio (FL/T), suggesting that a higher proinflammatory status is related to a higher FL/T ratio expression. Furthermore, baseline FL/T ratio could have a predictor role of patient's functionality 1 year after the illness onset, depending on whether patient is treated or not with antipsychotic drugs.ConclusionInflammatory processes, neurotrophic pathways and functional status of FEP patients seem to be related which is of great traslational relevance. Specific, the expression of the 2 isoforms of BDNF receptor should be taken into account before starting an antipsychotic drug treatment.Disclosure of interestThe authors have not supplied their declaration of competing interest.

In recent decades, the assessment of neurological soft signs (NSS) in patients with psychosis has become a subject of special interest. The study of the progression of NSS during adolescence will provide valuable information about the role of NSS as endophenotypes or biomarkers and about brain development at a stage in which brain maturation has not yet been completed.Neurological soft signs were assessed in a sample of 110 first episodes of early-onset psychosis (EOP) and 98 healthy children and adolescents at two different times in a 2-year follow-up period.Patients with EOP showed more NSS than controls both at baseline (p.001) and the 2-year follow-up (p.001). No differences were found in the number of signs among the different diagnostic subgroups (schizophrenia, bipolar disorder, and other psychoses). When we examined the changes in NSS over the follow-up, the reduction of NSS in the patients was greater than the controls for 'Motor coordination' (p = .032), 'Others' (p.001), and 'Total score' (p.001) of the NES.Despite the greater reduction of NSS in patients than in controls along the follow-up, patients still have more neurological signs than healthy controls; therefore, these signs may be considered a trait marker. NSS do not seem to be specific to schizophrenia as they are present in different EOPs.

Subjects with autism spectrum disorders (ASD) have more medical needs and more difficulties accessing health care services than the general population. Their verbal and non-verbal communication difficulties and particular behaviors, along with lack of expertise on the part of physicians and failure of the services to make adjustments, make it difficult for them to obtain an appropriate health care.PurposeTo describe a model for health care delivery in an ASD population.MethodReview of relevant literature and a discussion process with stakeholders leading to the design of a service to meet the specialty health needs of subjects of all ages with ASD for a region with a population of 6,000,000.ResultsA service was designed centred around the concepts of case management, individualization, facilitation, accompaniment, continuous training and updating, and quality management. Five hundred and thirteen patients with ASD have been seen over a period of 18 months. The programme generated 1566 psychiatric visits and 1052 visits to other specialties (mainly Nutrition, Stomatology, Neurology, and Gastroenterology) in the same period.ConclusionPersons with ASD may benefit from adjustments of health care services in order to improve their access to adequate health care at the quality level of the rest of the population.

Cognitive deficits are a core feature of psychotic disorders. Both in adult and adolescent populations, studies have shown that patients with psychosis have poorer cognitive functioning than controls. The cognitive domains that seem to be affected are mainly attention, working memory, learning and memory, and executive function. However, with regard to the trajectory of cognitive function throughout the illness, there is still a dearth of prospective data in patients who develop psychosis during adolescence. In this article, neuropsychological functioning was assessed in a sample of 24 first episodes of early onset psychosis (EOP) and 29 healthy adolescents at baseline and after a two-year follow-up. Patients with EOP showed lower scores than controls in overall cognitive functioning and in all specific domains assessed (attention, working memory, executive function, and learning and memory) both at baseline and the two-year follow-up. When changes in cognitive functioning over two years were assessed, patients and controls showed significant improvement in almost all cognitive domains. However, this improvement disappeared in the patient group after controlling for improvement in symptomatology. Our findings support a neurodevelopmental pathological process in this sample of adolescents with psychosis.

behavior compared with controls (n = 8, p< 0.01, Students t-test), indicating that they had remembered the initial FS test. No co-localization of c-Fos with BrdU was found in either group. The number of BrdU-positive neurons was higher in the dentate gyrus of the FS group (19.6±2.1 neurons, n = 8) than in control animals (12.0±1.1 neurons, n = 4) (p< 0.03, Student’s t-test). To investigate a role of GRs in the survival-promoting effect of FS we pre-treated rats with the GR antagonist RU486 before the initial FS challenge. RU486 impaired the behavioural immobility response in the 4-week retest (n = 7/group; p< 0.01, posthoc Bonferroni test) and abolished the FS-evoked increase in neuronal survival compared with the vehicle-pre-treated group (n = 5/control group, 7/FS group; p< 0.001, posthoc Bonferroni test). Thus, a single FS challenge promotes the survival of new adult-born DG granule neurons, which requires GR activation at the time of the stressful challenge and which may contribute to the formation of long-term memories of the FS event.

variance has been performed by group, age and IQ. Age, IQ and severity (CGI, C-GAS) effects were analyzed by Pearson’s correlation; single emotions by repeated measures. Statistical significance required two-tailed p 0.05. Results: Drug-free ADHD and ASD children were significantly slower than TDCs in both FR in FR (RTc: ASD p= 0.01, ADHD p< 0.001; RTe: ASD e ADHD p< 0.001) and IFE (RTc: ASD p= 0.001, ADHD p= 0.022; RTe: ASD p= 0.004). ASD were also slower compared with TDCs in MFE4 (RTc p = 0.039, RTe p = 0.05). Both drug-free ADHD and ASD appeared less accurate than TDCs in MFE4 (ASD p= 0.007, ADHD p= 0.002) and IFE (ASD p= 0.004, ADHD p= 0.005), but not in FR. When processing ‘surprise’, both the ASD and ADHD group exhibited longer RTc compared to TDCs (ASD p< 0.001, ADHD p= 0.018). MPH treatment induced a significant improvement in facial recognition abilities both in speed (RTc: p = 0.023) and accuracy (p< 0.001); increased accuracy has also been observed in IFE (p = 0.004) and MFE tasks (p< 0.001), especially in ‘Happiness’ recognition (p< 0.001). Discussion: The results suggest that specific information processing deficits during face recognition and identification of facial emotions stimuli are present in both ADHD and ASD compared to TDC, with some differences between them. These data highlight the utility, in both ADHD and ASD children, of specific neuropsychological tasks to better characterize strengths and difficulties in their cognitive/affective functioning, in order to develop specific and efficient treatment strategies. Preliminary results suggest that MPH facilitates emotion recognition, whilst not influencing processing speed, confirming recent evidence of MPH regulatory effect not only on inhibitory fronto–striatal circuitry but even its effect in attenuating abnormal activity within affective circuits involved in emotional processing [3].

C. Moreno1 °, R. Calvo-Escalona2, S. Gutierrez3, M. Graell3, J. Romo1, M.L. Dorado1, M.L. Giraldez1, C. Llorente1, C. Arango1, M. Parellada1 1Hospital General Universitario Gregorio Maranon, Child and Adolescent Psychiatry Department School of Medicine Universidad Complutense IiSGM CIBERSAM, Madrid, Spain; 2Hospital Clinic, Child and Adolescent Psychiatry and Psychology CIBERSAM, Barcelona, Spain; 3Hospital Universitario Nino Jesus, Child and Adolescent Psychiatry, Madrid, Spain

Background and aims:Psychosis with onset prior to 18 years of age, or early-onset psychosis (EOP), have a poorer prognosis than adult-onset psychosis. Further, a worse functional outcome of patients with EOP has been related to diagnosis of schizophrenia, severity of negative symptoms, behavioral problems, premorbid functioning, childhood onset, and insidious onset. We aim to examine the functional outcome of patients with EOP over a two-year follow-up.Methods:A total of 24 patients with first episode psychosis were enrolled. Subjects underwent a cross-sectional evaluation at the baseline visit that consisted of collecting sociodemographic data, including parental socioeconomic status as measured by the Hollingshead-Redlich Scale. Psychotic symptoms were assessed using the Spanish version of the Positive and Negative Syndrome Scale (PANSS). Social disability was measured with the Global Assessment of Functioning disability scale (GAF). Patients were assessed at a two-year follow-up. A linear regression analysis was used to predict the level of functioning (based on GAF scores) over the two-year follow-up. Variables entered into this equation were: GAF at two-year follow-up (as dependent variable), and gender, age at first onset, parental socioeconomic status, diagnosis, positive symptoms at baseline, and negative symptoms at baseline (as independent variables).Results:Negative symptoms at baseline were the only significant variable that predict the functional outcome at the two-year follow-up (p= 0.010).Conclusions:Functional prognosis of early-onset psychosis depends on the severity of negative symptoms, independently of diagnosis.

In previous work we developed a pharmacogenetic predictor of antipsychotic (AP) induced extrapyramidal symptoms (EPS) based on four genes involved in mTOR regulation. The main objective is to improve this predictor by increasing its biological plausibility and replication. We re-sequence the four genes using next-generation sequencing. We predict functionality “in silico” of all identified SNPs and test it using gene reporter assays. Using functional SNPs, we develop a new predictor utilizing machine learning algorithms (Discovery Cohort, N = 131) and replicate it in two independent cohorts (Replication Cohort 1, N = 113; Replication Cohort 2, N = 113). After prioritization, four SNPs were used to develop the pharmacogenetic predictor of AP-induced EPS. The model constructed using the Naive Bayes algorithm achieved a 66% of accuracy in the Discovery Cohort, and similar performances in the replication cohorts. The result is an improved pharmacogenetic predictor of AP-induced EPS, which is more robust and generalizable than the original.

This work was supported by the Spanish Ministry of Economy and Competiveness and the Carlos III Health Institute through CIBERSAM, and the Foundation Santander-UCM (GR 58/08), and partly supported by the Spanish Ministry of Economy and Competiveness directly, and by the European Regional Development Fund, FEDER (PI10/01746, PI11/01977, PI11/02708,PI12/02077), local grants from the Department of Education, Linguistic Policy and Culture of the Basque Country Government (2010111170, 2010112009), the Basque Foundation for Health Innovation and Research (BIOEF), ) and the University of the Basque Country (GIC10/80, GIC12/84)., Martinez-Cengotitabengoa, M., Macdowell, K.S., Alberich, S., Diaz, F.J., Garcia-Bueno, B., Rodriguez-Jimenez, R., Bioque, M., Berrocoso, E., Parellada, M., Lobo, A., Saiz, P.A., Matute, C., Bernardo, M., Gonzalez-Pinto, A., Leza, J.C.

Equitat en salut; Equity in Health; Equidad en salud L’equitat en salut ens ha de preocupar si considerem que tots els éssers humans són moralment iguals i que, per tant, mereixen el mateix respecte a la seva vida i dignitat. Però també és rellevant des d’una visió més utilitarista, atès que uns nivells pitjors de salut dels individus comprometen el benestar social i econòmic global de les comunitats. Així, doncs, l’aspiració a l’equitat no és només una qüestió d’altruisme o de bones intencions, sinó una obligació moral i una qüestió de dret.